Pausing Methotrexate Doubles COVID-19 Vaccine Response 

Taking a drug holiday increases antibodies as well as flare risks.

By Linda Rath | Sept. 24, 2022

Taking a two-week break from methotrexate after a COVID-19 booster shot more than doubles the response to the vaccine in people with autoimmune inflammatory diseases like rheumatoid arthritis (RA) and psoriasis, according to a 2022 study published in The Lancet Respiratory Medicine

Methotrexate is one of the most commonly prescribed drugs for inflammatory diseases, but because it suppresses the immune system, it blunts the effectiveness of vaccines. The American College of Rheumatology (ACR) has been recommending a one-week break from methotrexate after each COVID-19 shot, though the advice is based on a study of shots for flu and pneumonia, not COVID-19. The ACR’s stance is also controversial, with some experts arguing against risking a flare by interrupting methotrexate treatment.
Given the uncertainty, researchers in the U.K. decided to see whether pausing methotrexate after a COVID-19 booster could stimulate a more robust vaccine response while lowering the chance of potential flares and safeguarding overall health.

The Trial

The VROOM trial (short for vaccine response on/off methotrexate) was a randomized controlled trial with 254 initial participants. Most were women, and most were around 60 years old.  One hundred thirty people in the trial had RA and 86 had psoriasis or psoriatic arthritis (PsA). All had been receiving less than 25 mg of methotrexate a week for at least three months.

Half the participants were randomly assigned to continue taking methotrexate as usual and half to stop it for two weeks right after an mRNA booster from Pfizer or Moderna. People who stopped methotrexate continued to take other medications, such as hydroxychloroquine or folic acid.

What the Trial Showed

The group who took a two-week methotrexate holiday developed significantly more antibodies to the coronavirus than the group who didn’t. Their antibodies remained high after three months, no matter what their age, disease, vaccine type and whether they’d had COVID-19. 

People who paused methotrexate also had higher disease activity from their autoimmune condition and reported more flares in the first month than people who continued to take the drug. Most flares weren’t serious, were usually self-managed and didn’t affect overall health. 

The VROOM trial results echo those of other recent studies. Researchers in India, for example, showed that pausing methotrexate after the first and second doses of the AstraZeneca vaccine, which isn’t approved in the U.S., led to much higher antibody levels than in people who didn’t stop the drug. And stopping after just the second dose reduced the risk of flares. 

Both studies have limitations. They’re relatively small, they excluded people who weren’t able to stop methotrexate, and they didn’t show that a drug holiday increased T-cell response, which is critical for long-term virus protection. Still, researchers say a methotrexate pause may be a safe, simple and effective way to boost the initial vaccine response in people with RA and other inflammatory types of arthritis.